The heptadecapeptide nociceptin is an endogenous ligand of the ORL1 (Opioid-Receptor-Like) receptor (Meunier et al., Nature 377, 1995, pp. 532–535), which belongs to the family of opioid receptors and may be found in many regions of the brain and the spinal cord (Mollereau et al., FEBS Letters, 341, 1994, pp. 33–38, Darland et al., Trends in Neurosciences, 21, 1998, pp. 215–221). The peptide is characterized by a high affinity, with a Kd value of approximately 56 pM (Ardati et al., Mol. Pharmacol. 51, pp. 816–824), and by high selectivity for the ORL1 receptor. The ORL1 receptor is homologous to the μ, κ and δ opioid receptors and the amino acid sequence of the nociceptin peptide has a marked similarity to those of the known opioid peptides. The activation of the receptor induced by the nociceptin leads, via the coupling with Gi/o proteins to inhibition of the adenylate cyclase (Meunier et al., Nature 377, 1995, pp. 532–535). On the cellular plane also, there are functional similarities between the μ, κ and δ opioid receptors and the ORL1 receptor with respect to activation of the potassium channel (Matthes et al., Mol. Pharmacol. 50, 1996, pp. 447–450; Vaughan et al., Br. J. Pharmacol. 117, 1996, pp. 1609–1611) and inhibition of the L-, N- and P/Q-type calcium channels (Conner et al., Br. J. Pharmacol. 118, 1996, pp. 205–207; Knoflach et al., J. Neuroscience 16, 1996, pp. 6657–6664).
After intercerebroventicular application, the nociceptin peptide exhibits pronociceptive and hyperalgesic activity in various animal models (Reinscheid et al., Science 270, 1995, pp. 792–794; Hara et al., Br. J. Pharmacol. 121, 1997, pp. 401–408). These findings may be explained as inhibition of stress-induced analgesia (Mogil et al., Neurosci. Letters 214, 1996, pp. 131–134; and also Neuroscience 75, 1996, pp. 333–337). In this connection, anxiolytic activity of the nociceptin could also be demonstrated (Jenck et al., Proc. Natl. Acad. Sci. USA 94, 1997, 14854–14858).
On the other hand, an antinociceptive effect of nociceptin could be demonstrated in various animal models, in particular after intrathecal administration. Nociceptin inhibits the activity of kainate- or glutamate-stimulated dorsal root ganglion neurons (Shu et al., Neuropeptides, 32, 1998, 567–571) or glutamate-stimulated spinal cord neurons (Faber et al., Br. J. Pharmacol., 119, 1996, pp. 189–190); it has an antinociceptive effect in the tail flick test in mice (King et al., Neurosci. Lett., 223, 1997, 113–116), in the flexor-reflex model in rats (Xu et al., NeuroReport, 7, 1996, 2092–2094) and in the formalin test on rats (Yamamoto et al., Neuroscience, 81, 1997, pp. 249–254). In models of neuropathic pain, an antinociceptive effect of nociceptin, which is of interest in so far as the effectiveness of nociceptin increases after axotomy of spinal nerves, could be demonstrated (Yamamoto and Nozaki-Taguchi, Anesthesiology, 87, 1997). This is in contrast to conventional opioids, of which the effectiveness decreases under these conditions (Abdulla and Smith, J. Neurosci., 18, 1998, pp. 9685–9694).
The ORL1 receptor also participates in the regulation of further physiological and pathophysiological processes. These include learning and memory formation (Sa{dot over (n)}din et al., Eur. J. Neurosci., 9, 1997, pp. 194–197; Manabe et al., Nature, 394, 1997, pp. 577–581), hearing ability (Nishi et al., EMBO J., 16, 1997, pp. 1858–1864), assimilation of food (Pomonis et al., NeuroReport, 8, 1996, pp. 369–371), regulation of blood pressure (Gumusel et al., Life Sci., 60, 1997, pp. 141–145; Campion and Kadowitz, Biochem. Biophys. Rep. Comm., 234, 1997, pp. 309–312), epilepsy (Gutierrez et al. Abstract 536.18, Society for Neuroscience, Vol. 24, 28th Ann. Meeting, Los Angeles, 7–12 Nov. 1998) and diuresis (Kapisa et al., Life Sciences, 60, 1997, PL 15–21). In an article by Calo et al. (Br. J. Pharmacol., 129, 2000, 1261–1283) an overview is given of the indications or biological processes in which the ORL1 receptor plays a part or could very probably play a part. These include: analgesia, stimulation and regulation of food assimilation, influence on μ agonist such as morphine, treatment of withdrawal symptoms, reduction of addiction potential of morphines, anxiolysis, modulation of movement activity, memory defects, epilepsy; modulation of neurotransmitter discharge, in particular of glutamate, serotonin and dopamine, and therefore neurodegenerative diseases; influencing of the cardiovascular system, triggering of an erection, diuresis, antinatriuresis, electrolyte management, arterial blood pressure, water retention diseases, intestinal motility (diarrhea), relaxing effects on the respiratory tracts, micturation reflex (urinary incontinence). The use of agonist and antagonist as anoretics, analgesics (also in co-administration with opioids) or nootropics, but also as antitussives is also discussed.
The possible applications of compounds which bind to the ORL1 receptor and activate or inhibit it are correspondingly varied.